Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4.
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Kalgutkar AS, Henne KR, Lame ME, Vaz AD, Collin C, Soglia JR, Zhao SX, Hop CE
Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4.
Chem Biol Interact. 2005 Jun 30;155(1-2):10-20. Epub 2005 Apr 18.
- PubMed ID
- 15978881 [ View in PubMed]
- Abstract
Therapy with the antidepressant trazodone has been associated with several cases of idiosyncratic hepatotoxicity. While the mechanism of hepatotoxicity remains unknown, it is possible that reactive metabolites of trazodone play a causative role. Studies were initiated to determine whether trazodone undergoes bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing trazodone and NADPH-supplemented microsomes or recombinant P4503A4 in the presence of glutathione revealed the formation of conjugates derived from the addition of the sulfydryl nucleophile to mono-hydroxylated- and hydrated-trazodone metabolites. Product ion spectra suggested that mono-hydroxylation and sulfydryl conjugation occurred on the 3-chlorophenyl-ring, whereas hydration and subsequent sulfydryl conjugation had occurred on the triazolopyridinone ring system. These findings are consistent with bioactivation sequences involving: (1) aromatic hydroxylation of the 3-chlorophenyl-ring in trazodone followed by the two-electron oxidation of this metabolite to a reactive quinone-imine intermediate, which reacts with glutathione in a 1,4-Michael fashion and (2) oxidation of the pyridinone ring to an electrophilic epoxide, ring opening of which, by glutathione or water generates the corresponding hydrated-trazodone-thiol conjugate or the stable diol metabolite, respectively. The pathway involving trazodone bioactivation to the quinone-imine has also been observed with many para-hydroxyanilines including the structurally related antidepressant nefazodone. It is proposed that the quinone-imine and/or the epoxide intermediate(s) may represent a rate-limiting step in the initiation of trazodone-mediated hepatotoxicity.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Trazodone Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details
